Lung cancer is more prevalent in African Americans as compared to European Americans, and cigarette smoking is the major risk factor in both these groups. Tobacco-specific nitrosamines are among the most significant carcinogens in tobacco products. One ofthe most prevalent of these compounds, 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is present in both unburned tobacco and cigarette smoke, and is a remarkably effective lung carcinogen in laboratory animals, inducing lung tumors in rodents independent ofthe route of administration. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a metabolite of NNK, is also a pulmonary carcinogen, and its serum levels are related to lung cancer in smokers. Metabolism and DNA adduct formation are critical in cancer induction by NNK. Our goal is to understand whether the observed ethnic/racial differences in lung cancer incidence are due to variations in NNK metabolism. Our overall hypothesis is that cancer susceptibility relates to carcinogen dose and to the balance between carcinogen metabolic activation and detoxification. Our specific aims are: 1) Conduct a comprehensive analysis of urinary biomarkers of NNK metabolic activation and detoxification in African American and European American smokers. This research builds on our recently developed methodology based on the use of deuterium-labeled NNK. 2) Measure in exfoliated oral mucosa cells of African American and European American smokers DNA adducts formed as a result of NNK metabolic activation. This is critical to an understanding of the balance between the urinary excretion of NNK metabolites and the extent of NNK DNA binding. In the future, this balance could serve as a direct indicator of cancer susceptibility in humans. 3) Investigate the relationship between levels of NNK-derived DNA adducts measured in oral mucosa cells and the rates of repair of these adducts in cultured lymphocytes from our subjects. This research will complement the results obtained in Specific Aims 1 and 2. In summary, the results of these experiments will provide exciting new data on differences in NNK metabolic activation and detoxification, as well as formation of NNK-derived DNA adducts and related DNA repair capacity in African Americans and European Americans. This will also help to test the overall hypothesis that differences in the mechanisms of NNK carcinogenesis are related to lung cancer susceptibility in humans.